Mitochondrial Toxicity, Lactate Levels

Special report for NATAP from Kees Brinkman, MD, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

Although the special focus of this conference was not especially directed on treatment issues such as long-term toxicities, several reports were presented on mitochiondrial toxicity. In short, mitochondrial toxicity is an acquired decrease in mitochondrial function (mitochonria are an important element in cells) induced by NRTIs. This decrease in function can result in several clinical syndromes like myopathy, neuropathy and lactic acidosis. Of special concern is the issue whether such toxicity can lead to (irreversible?) damage to a developing child, if it is exposed to NRTIs during pregnancy

Mitochondrial toxicity & newborns. Several authors addressed the issue of perinatally induced mitochondrial toxicity. Launay et al. (Creteil France) reported 2 cases of transitory lactic acidosis in children with antiretroviral exposure around birth. Gabioni et al. (Turin Italy) described a neonate with clear symptoms of mitochondrial disease with depletion of mitochondrial DNA, related to AZT exposure during pregnancy. Chotpitayasunondh et al (Bangkok Thailand) could not find any clinical case of mitochondrial dysfunction in a prospective study of 395 children (196 AZT exposed), and also other cohorts were unable to find serious toxicities during prevention studies of Mother to Child Transmission.

Mitochondrial Toxicity & Lipodystrophy. Regarding the possible role of mitochondrial toxicity in the induction of lipodystrophy syndrome, especially lipoatrophy, Mallal and Nolan (Perth Australia) showed in the late breaker poster session on Thursday impressive electron microscopy pictures of adipose tissue, taken from patients with clear symptoms of lipodystrophy. Both in patients treated with or without protease inhibitors (but always NRTIs), there were clear abnormalities in mitochondrial structure, together with an accumulation of lipid droplets (steatosis), compared with control specimens. Furthermore, there was an unexplained deposition of granular material on the inner aspect of the adipocyte membrane.

Lactate Levels. Harris et al. (Vancouver Canada) and Vrouenraets et al. (Amsterdam The Netherlands), presented data on the relatively frequent (19 36%) occurrence of mildly elevated levels of lactic acid in NRTI treated patients. An increased risk was found for patients on d4T treatment. The significance of such a finding is not known so far and during the oral poster presentation, it was emphasised that lactates below 5 mmol/L should not be used as an argument to change treatment in asymptomatic patients. Routine lactate measurements should therefore be implemented with caution, to avoid unnecessary treatment alterations. (Added commentary from Jules Levin: Mild elevations in lactate levels are not uncommon for a patient on HIV treatment, but without symptoms, it remains uncertain what to do about it. Symptoms of lactic acidosis, which include fatigue & nausea, are unusual but might necessitate treatment cessation. It is suggested that elevated lactate could reflect impaired mytochondria and might be related to body changes associated with lipodystrophy).

Human Growth Hormone. Engelhard from Serono Labs, the manufactuer of HGH, reported on 8 patients with HARS ( HIV Associated Adipose Redistribution Syndrome) who received 5-6 mg/qd subc. injection HGH while staying on therapy, 4 on PI regimens for an average of 12 months. They reported decreased abdominal girth of 4.8 centimeters. Six patients with buffalo hump had a decrease of about 1 grade in size.

A Swiss research group reported on HIV infected patients (3 females) with fat accumulation who were randomized and double-blinded to 3 months of daily placebo or 6 mg subc., and then each group was crossed over to the other. For both groups there was a mean loss of trunk fat (by DEXA) of 2.40 kg. There was a gain of trunk fat during the placebo treatment, which may be due to rebound from stopping the HGH. Adverse events appear to be fairly common across studies. One person withdrew after 4 weeks because of swelling and dysesthesia of the feet. HGH was associated with side effects in 6/7 individuals: mainly swelling, pain, and dysesthesia in hands and feet. After 3 months of HGH, 1 patient developed diabetes and elevated triglycerides. Side effects appear to resolve upon discontinuation, but a person with diabetes should not take HGH.

Engelson & Kotler reported on a prospective, open-label trial of 6 mg/day HGH s.c. of 14 HIV-infected individuals with fat redistribution and enlarged abdomen. HGH treatment was for 24 weeks and there was a 12-week follow-up after stopping HGH. There was a fat loss of about 5-kg, overall weight was about the same. Although there was a loss in trunk fat, there was also a loss in arm and leg fat by DEXA. Visceral adipose tissue (deep stomach fat) was reduced as measured by MRI. The effects were complete by week 12. 12 weeks after HGH was stopped 85% of the visceral adipose tissue (deep stomach fat) returned, and the farm & leg at loss returned. Adverse effects were common, especially arthralgias and myalgias that improved or resolved with dose reduction or discontinuation. In addition, at week 12, 3 participants (13%) met American Diabetes Association criteria for diabetes based on a 2-hour oral glucose tolerance test and 9 patients (30%) met the criteria for glucose intolerance. Although all 30 participants had normal fasting glucose at baseline, they also all had elevated fasting insulins (>10 IU/mL). Lower doses and induction-maintenance dosing will be explored in future study.